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Human Molecular Genetics Advance Access published online on September 20, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl252
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received June 9, 2006
Revised September 7, 2006
Accepted September 7, 2006

Article

Cholinergic neuronal defect without cell loss in Huntington's disease

Ruben Smith 1, Hinfan Chung 1, Sara Rundquist 1, Marion L.C. Maat-Schieman 2, Lesley Colgan 3, Elisabet Englund 4, Yong-Jian Liu 3, Raymund A.C. Roos 2, Richard L.M. Faull 5, Patrik Brundin 1, and Jia-Yi Li 1 *

1 Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 221 84 Lund, Sweden
2 Department of Neurology, LUMC, 2300 Leiden, The Netherlands
3 Departments of Neurology and Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
4 Department of Clinical Science, Lund, Division V, Pathology, University Hospital, 221 84 Lund, Sweden
5 Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, The University of Auckland, 92019 Auckland, New Zealand

* To whom correspondence should be addressed.
Jia-Yi Li, E-mail: jia-yi.li{at}med.lu.se


  Abstract

Huntington's Disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (IT15) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium sized spiny neurons. Traditionally the large cholinergic striatal interneurons are believed to be spared. Recent studies demonstrate that neuronal dysfunction without cell death also plays an important role in early and mid-stages of the disease. Here we report that cholinergic transmission is affected in a HD transgenic mouse model (R6/1) and in tissues from HD patients. Stereological analysis shows no loss of cholinergic neurons in the striatum or septum in R6/1 mice. In contrast, the levels of mRNA and protein for vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) are decreased in the striatum and cortex, and acetylcholine esterase (AChE) activity is lowered in the striatum of R6/1 mice already at young ages. Accordingly, VAChT is also reduced in striatal tissue from patients with HD. The decrease of VAChT in the patient samples studied is restricted to the striatum, and does not occur in the hippocampus or the spinal cord. The expression and localization of REST/NRSF, a transcriptional regulator for the VAChT and ChAT genes, are not altered in cholinergic neurons. We show that the R6/1 mice exhibit severe deficits in learning and reference memory. Taken together, our data show that the cholinergic system is dysfunctional in R6/1 and HD patients. Consequently, they provide a rationale for testing of pro-cholinergic drugs in this disease.


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